Nerve cell function is greatly influenced by the contact between the neuron and other cells in its immediate environment (U. Rutishauser, T. M. Jessell, Physiol. Rev. 68:819 (1988)). These cells include specialized glial cells, oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS), which ensheathe the neuronal axon with myelin (an insulating structure of multi-layered membranes) (G. Lemke, in An Introduction to Molecular Neurobiology, Z. Hall, Ed. (Sinauer, Sunderland, Mass.), p. 281 (1992)).
While CNS neurons have the capacity to regenerate after injury, they are inhibited from doing so because of the presence of inhibitory proteins present in myelin and possibly also by other types of molecules normally found in their local environment (Brittis and Flanagan, Neuron 30:11-14 (2001); Jones et al., J. Neurosc. 22:2792-2803 (2002); Grimpe et al., J. Neurosci. 22:3144-3160 (2002)). Thus, nervous system diseases or injuries, such as spinal cord injury (SCI), traumatic brain injury, or chronic deficits after stroke, cause profound and persistent neurological deficits. Much of the disability below the level of injury is due to the interruption of axonal connectivity.
Myelin plays a role in interrupting axonal connectivity by limiting axonal growth and neurological recovery after SCI (B. P. Liu et al., Philos. Trans. R. Soc. Lond. B. Biol. Sci. 361:1593-1610 (2006)). Amongst the inhibitory myelin proteins are Nogo-A (Rtn4A) (Chen et al., Nature 403:434-439 (2000); Grandpre et al., Nature 403:439-444 (2000)), myelin associated glycoprotein (MAG, Siglec-4) (McKerracher et al., Neuron 13:805-811 (1994); Mukhopadhyay et al., Neuron 13:757-767 (1994)), and oligodendrocyte myelin glycoprotein (OMgp) (Mikol and Stefansson, J. Cell. Biol. 106:1273-1279 (1988)).
Each of these proteins has been separately shown to be a ligand for the neuronal Nogo receptor-1 (NgR1, Rtn4R) protein expressed by axons (Wang et al., Nature 417:941-944 (2002); Liu et al., Science 297:1190-93 (2002); Grandpre et al., Nature 403:439-444 (2000); Chen et al., Nature 403:434-439 (2000); Domeniconi et al., Neuron 35:283-90 (2002); X. Wang et al., Ann. Neurol. 60:540-49 (2006)). NgR1 is a glycophosphatidylinositol (GPI)-anchored membrane protein that contains eight leucine rich repeats (Fournier et al., Nature 409:341-346 (2001)). Upon interaction with an inhibitory protein, e.g., NogoA, MAG and OMgp, the NgR1 complex transduces signals that lead to growth cone collapse and inhibition of neurite outgrowth.
Recent advances have identified compounds that protect neuronal elements immediately after injury and/or stimulate the growth of axons when administered within several days of SCI (S. Rossignol et al., J. Neurosci. 27:11782-92 (2007); B. P. Liu et al., Philos. Trans. R. Soc. Lond. B. Biol. Sci. 361:1593-1610 (2006)). For example, soluble NgR1(310)ecto-Fc protein infused into the CNS within a week of spinal cord dorsal hemisection, stroke, or spinal cord contusion increases axonal growth responses and improves behavioral recovery (S. Li et al., J. Neurosci. 24:10511-20 (2004); J. K. Lee et al., J. Neurosci. 24:6209-17 (2004); D. M. Basso et al., J. Neurotrauma 12:1-21 (1995)).
Clinical trials are now testing the efficacy of compounds that block myelin inhibitors in these instances of acute nervous system disease or injury, such as acute SCI (S. Rossignol et al., J. Neurosci. 27:11782-92 (2007). However, because SCI frequently occurs in young adults and improved supportive care has dramatically increased life expectancy, the prevalence of chronic SCI is more than twenty times the annual incidence of acute SCI (A. E. Fournier et al., Nature 409:341-46 (2001)). Neuroprotective strategies are clearly too late to benefit chronic SCI, and axonal growth promoting strategies have only shown benefit during the acute, after-injury period. Thus, therapeutic advances for acute spinal cord injuries have been considered incapable of re-activating axonal growth and recovery in the much more prevalent condition of chronic SCI. The prevailing opinion is that blockade of axonal growth inhibitors can be beneficial only in a time frame close to the trauma, when the injured axon has the highest potential for growth. This leaves cellular transplantation, but not pharmacological intervention, as the only therapeutic potential for chronic SCI.
Therefore, there exists an urgent need for therapeutic methods for treating chronic nervous system diseases or injuries, including chronic SCI, and for non-invasive methods of monitoring said treatment.